A novel orally administered macrophage delivered gene therapy is being developed to address the present therapeutic limitations in treating Gaucher Disease. The skeletal and central nervous system complications of Gaucher disease still present an enormous challenge for current enzyme and gene replacement therapies. Despite the successes of gene therapy strategies in animal models, the clinical trials conducted to date have generally resulted in either low levels of gene expression or a failure of engraftment. In this study, an orally administered formulation of yeast cell wall particles (YCWP) containing DMA encoding human glucocerebrosidase is used to restore human glucocerebrosidase activity in macrophages of Gaucher mice. To accomplish this goal we will: 1) orally administer formulations of YCWP containing DNA encoding human glucocerebrosidase to long-lived L444P Gaucher mice that have clinical manifestations similar to those observed in patients with Gaucher disease; 2) determine the extent of improvement in enzyme levels in macrophages and tissues of treated Gaucher mice; 3) determine the extent of reversal of lipid storage and tissue pathology, and impact on survival; and, 4) identify the location and degree that macrophages in bone and brain are expressing human glucocerebrosidase. Through this study we will determine parameters that will be used for in-vivo optimization of human glucocerebrosidase expression by this orally administered macrophage delivered gene therapy. In addition to improved delivery of human glucocerebrosidase to many tissues, including bone and brain, we expect that this approach will achieve significant reversal of tissue pathology in treated L444P Gaucher mice. If macrophages containing human glucocerebrosidase migrate into brain, the resulting increased enzyme levels could provide clinical benefit for the neurological manifestations of Gaucher disease. The successful development of this innovative therapeutic strategy should provide a safer, more efficient and cost effective treatment for patients with Gaucher disease, as well as providing a prototype of therapy to benefit those having a wide range of other lysosomal diseases.